This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The hydrophobic match between transmembrane domains and the lipid bilayer has been recognized as a central feature in protein-lipid interactions and bilayer regulation of membrane protein functions. Traditionally, people have envisioned that a transmembrane helix may tilt or kink in order to overcome unfavorable interactions arising from a hydrophobic mismatch. To determine the microscopic forces governing the helix tilting in membranes, we have recently calculated the potential of mean force as a function of tilt angle of WALP19, a transmembrane model peptide, in a DMPC membrane. The total potential of mean force and its decomposition reveal that the helix tilting in membranes is governed by interplay between an intrinsic entropy contribution arising from the helix precession around the membrane normal and the sequence- and length-specific helix-lipid interactions. Based on this novel view on helix tilting in membranes, we propose to extend the calculations of potentials of mean force to enrich our understanding of the influence of a hydrophobic mismatch on transmembrane helix tilting. The role of specific helix-lipid interactions in the helix tilting will be determined by performing potential of mean force calculations with transmembrane helices with different hydrophobic lengths, different anchoring residues at the membrane interface, and lipid bilayers with different hydrophobic thicknesses.